1. Field of the Invention
The present invention relates to quinolone compounds useful as medicines, veterinary medicines, fishery medicines, or antibacterial preservatives.
2. Description of the Related Art
Since the discovery of norfloxacin, quinolone synthetic antibacterial agents (including those having a pyridobenzoxazine skeleton) with improved antibacterial activity and pharmacokinetics have been developed into chemotherapeutic agents effective for almost all systemic infections, and many of them are now clinically used (see Japanese Patent Laid-Open No. 61-282382 or Japanese Patent Laid-Open No. 63-45261 and Clinical Microbiology and Infection, Vol. 11, No. 4, p. 256 (2005)).
However, the number of types of bacteria having low sensitivity to quinolone synthetic antibacterial agents has tended to increase in the clinical field in recent years. For example, the number of types of bacteria resistant to drugs other than quinolone synthetic antibacterial agents, which are so-called multidrug-resistant bacteria, such as Gram-positive cocci including Staphylococcus aureus (methicillin-resistant Staphylococcus aureus: MRSA) and pneumococcus (penicillin-resistant Streptococcus pneumonia: PRSP) having low sensitivity to β-lactam antibiotics; and enterococci having low sensitivity to aminoglycoside antibacterial agents (vancomycin-resistant enterococcus: VRE) and having also low sensitivity to quinolone synthetic antibacterial agents has increased. Bacterial infections caused by such resistant Gram-positive bacteria are known to be generally severe (fatal) and intractable. Accordingly, drugs more effective to Gram-positive cocci are particularly desired in the clinical field (see Drugs, Vol. 66, No. 6, p. 751 (2005)).
On the other hand, quinolone synthetic antibacterial compounds created in recent years have antibacterial activities that are much higher than those of previous ones (see Japanese Patent Laid-Open No. 2-231475 or Japanese Patent Laid-Open No. 3-95176). However, many of such quinolone compounds having high antibacterial activity cause side effects based on their physiological and pharmacological effects not observed for previous quinolone synthetic antibacterial agents.
Examples of the side effects of quinolone synthetic antibacterial agents include conventionally reported side effects such as induction of convulsion by use in combination with non-steroidal anti-inflammatory drugs (NSAIDs), central actions (mild central nervous system disorders such as sway, headache, and insomnia, and serious side effects such as the onset of fatal convulsion), and phototoxicity (photosensitivity); as well as recently disclosed side effects such as hepatotoxicity (serious allergic hepatitis), cardiotoxicity (electrocardiographic abnormality inducing fatal arrhythmia, observed as QT or QTc prolongation), delayed drug eruption (skin rash), and blood glucose level abnormality (see Hiroyuki Kobayashi (ed.), Clinical Application of New Quinolone Agents, Iyaku (Medicine and Drug) Journal Co., Ltd.; Drugs, Vol. 62, No. 1, p. 13 (2002); Toxicology Letters, Vol. 127, p. 269 (2002); Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)); and International Journal of Antimicrobial Agents, Vol. 23, No. 5, p. 421 (2004)).
The clinical onset of cardiotoxicity among such side effects is a particular problem in recent years. Distinct QT or QTc prolongation is reported and some serious conditions (electrocardiographic abnormality inducing fatal arrhythmia) are also reported for some commercially available quinolone synthetic antibacterial agents (such as grepafloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and gemifloxacin). Serious side effects such as the onset of serious allergic hepatitis accompanying liver transplantation (trovafloxacin: see Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)) and blood glucose level abnormality including fatal hypoglycemia (gatifloxacin: see International Journal of Antimicrobial Agents, Vol. 23, No. 5, p. 421 (2004)) are also clinical problems. Further, delayed drug eruption (skin rash) caused by repeated administration of a quinolone agent in a clinical test (gatifloxacin: see Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)) is reported. In such circumstances, the administration of some quinolone synthetic antibacterial agents has been limited, and the development and use as human medicines of some quinolone synthetic antibacterial agents has been abandoned. That is, some quinolone synthetic antibacterial agents have been observed which have strong antibacterial activity but which in terms of side effects are not sufficiently suitable as medicines.
Accordingly, there is a need for safer quinolone synthetic antibacterial agents for use as human medicines, having only low side effects such as induction of convulsion by use in combination with non-steroidal anti-inflammatory drugs, central actions, and phototoxicity (photosensitivity) which are conventionally known as side effects; as well as cardiotoxicity, hepatotoxicity, delayed drug eruption (skin rash), and blood glucose level abnormality which are clinical problems in recent years. Therefore, there is a need for the development of compounds conceptually different from conventional compounds that have high antibacterial activity but cause side effects and thus cannot be used as medicines. That is, there is a need for quinolone compounds having both strong antibacterial activity and high safety (see The Japanese Journal for History of Pharmacy, Vol. 38, No. 2, p. 161 (2003)).
Antibacterial activity, pharmacokinetics, and safety of a quinolone synthetic antibacterial agent are known to be influenced by the structure of the substituents at each position of the quinolone skeleton, in particular, the structure of the substituent at the 7-position (corresponding to the 10-position of the pyridobenzoxazine skeleton) (see Clinical Microbiology and Infection, Vol. 11, No. 4, p. 256 (2005), for example).
The characteristic feature of the compounds of the present invention is that they have, at the 7-position of the quinolone mother skeleton, a substituent represented by the following formula 1:
wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in claim 1. That is, the 7-position substituent in the compounds of the present invention has a fused bicyclic amine structure that is formed by fusion of the pyrrolidine ring with a cyclic structure formed by taking R6 and R7 together with the carbon atoms to which they are bonded, and further the fused bicyclic amine structure has an amino group at the bridgehead position. In relation to quinolone derivatives substituted with a 7-position substituent having such a structure, the following compounds are known.
For example, Japanese Patent Laid-Open No. 64-56673 describes a pyridonecarboxylic acid derivative represented by the general formula 2:
wherein R represents a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a phenyl group which may have a substituent; X represents a nitrogen atom or C-A, wherein A represents a hydrogen atom or a halogen atom; Y represents a hydrogen atom or a halogen atom; and Z represents a group represented by the following formula 3:
wherein R1 represents a hydrogen atom, a lower alkyloxycarbonyl group, or an acyl group which may be substituted with a halogen atom; two of R2, R3, R4, and R5 are bonded directly or through a lower alkyl chain to form a ring and the remaining two of R2, R3, R4, and R5 each represents a hydrogen atom; and n represents 0 or 1, provided that R2 and R3 are a bond when these are bonded to each other. The definitions of substituents and the like in the compound represented by the formula 2 do not apply to the compounds of the present invention although the same symbols are used. However, Japanese Patent Laid-Open No. 64-56673 does not specifically disclose a quinolone compound in accordance with the present invention wherein R4 and R5 in the formula 3 are taken together to form a four- to seven-membered ring and n=0.
EP-A-343524 discloses a pyridonecarboxylic acid antibacterial agent represented by the general formula 4:
wherein R1 is hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, oxo, halogen, or amino which may optionally be substituted with C1-C4 alkyl and/or C1-C4 alkanoyl; R2 is azide, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkanoyl, or amino which may optionally be substituted with C1-C4 alkyl and/or C1-C4 alkanoyl; A is a quinolone structure represented by the following formula 5:
R3 is hydrogen or a carboxy protecting group; R4 is C1-C4 alkyl, C2-C5 alkenyl, C3-C5 cycloalkyl, mono- or di-fluorophenyl, or a five- or six-membered heterocycle which may optionally be substituted with halogen and/or C1-C4 alkyl; R5 is hydrogen, amino, hydroxy, or C1-C4 alkoxy; R6 is halogen; X is CH—(C1-C4 alkyl), C═CH2, N—H, or N—(C1-C4 alkyl); Z is CQ or N; Q is hydrogen, C1-C4 alkoxy, halogen, C1-C4 alkyl, or cyano; m is an integer of 0 or 1; and n and p are each an integer of 1 to 3. However, as a specific compound related to the compounds of the present invention, EP-A-343524 discloses only a quinolonecarboxylic acid derivative represented by the following formula 6, that is, a derivative in which m is 0, p is 1, and the substituent R2 is an amino group at the bridgehead position of the bicyclic amine:

Moreover, EP-A-343524 does not disclose a compound having a halogenocyclopropyl group at the 1-position which is a typical example of the compounds of the present invention. The structure of the 7-position substituent is a (1R*,5S*)-configuration in the compound represented as the formula 6 as disclosed in EP-A-343524. This compound is a so-called cis-racemate, and EP-A-343524 does not describe the antibacterial activity of an optical isomer. Further, EP-A-343524 does not describe the safety of the disclosed compound. A stereochemically single compound is preferable as a human medicine in terms of effectiveness and safety. In addition, the compound represented by the formula 6 has a fluorine atom at the 8-position of the quinolone skeleton and is thus presumed to cause phototoxicity (photosensitivity) with high probability (see Journal of Antimicrobial Chemotherapy, Vol. 33, p. 683 (1994), for example). That is, the compound represented by the formula 6 is not thought to be necessarily sufficient as a medicine for effective use in humans with safety. European Journal of Medicinal Chemistry, Vol. 26, p. 889 (1991) only describes the content in accordance with EP-A-343524.
WO 95/21163 discloses a pyridonecarboxylic acid antibacterial agent substituted with a bicyclic amino group, which is represented by the following general formula 7:
wherein R1 and R2 are the same or different and each represents a hydrogen atom, a lower alkyl group, or an amino-protecting group; R3 and R4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a lower alkoxy group, or a lower alkyl group; n represents an integer of 0 or 1; R5 represents a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl group, or a heterocyclic group (these may be further substituted); G represents C-E, wherein E represents a hydrogen atom or together with R5 forms a crosslinkage represented by —S—SE(CH3)—; T represents C—Z or a nitrogen atom, wherein Z represents a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group, or a halogeno lower alkyl group or together with R5 forms a crosslinkage represented by —O—CH2—CH(CH3)—; X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, or an amino group which may be protected; and D represents C—Y, wherein Y represents a hydrogen atom or a halogen atom. However, in relation to the compounds of the present invention, as a bicyclic amino group in the 7-position substituent of the quinolone derivative, only the substituent represented by the following formula 8, that is where R3 and R4 are each a hydrogen atom in the formula 7 and n is 0, is specifically disclosed:

Further, WO 95/21163 does not specifically disclose a fused substituted aminopyrrolidine derivative (bicyclic amine) which is a feature of the present invention, that is where in the compound represented by the formula 7 one or both of the substituents R3 and R4 on the bicyclic amine has a substituent other than a hydrogen atom.
WO 96/23782 discloses a N1-(halogenocyclopropyl) substituted pyridonecarboxylic acid derivative represented by the general formula 9:
wherein X1 represents a halogen atom or a hydrogen atom; X2 represents a halogen atom; R1 represents a hydrogen atom, a hydroxy group, a thiol group, a halogenomethyl group, an amino group, an alkyl group, or an alkoxy group; R2 represents a substituent of formula 10:
wherein R3 and R4 each represents a hydrogen atom or an alkyl group and n represents an integer of 1 or 2; A represents a group of formula 11:
wherein X3 represents a hydrogen atom, a halogen atom, a cyano group, an amino group, an alkyl group, a halogenomethyl group, an alkoxy group, or a halogenomethoxy group; and R represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group, an alkoxymethyl group, or a phenyl group. The definitions of substituents and the like in the compound represented by the formula 9 do not apply to the compounds of the present invention although the same symbols are used. However, in relation to the compounds of the present invention, as a bicyclic amino group in the 7-position substituent of the quinolone derivative, only the substituent represented by the following formula 12, that is where n is 2 in the formula 10, is specifically disclosed:

Further, WO 96/23782 does not disclose a 1-amino-3-azabicyclo[3.2.0]heptane derivative having a substituent other than a hydrogen atom on the bicyclic ring, which is a feature of the compounds of the present invention.
Japanese Patent Laid-Open No. 8-225567 discloses a quinolone- or naphthylidone-carboxylic acid derivative represented by the general formula 13:T-Q  [Formula 13]wherein Q represents a quinolone structure of formula 14:
wherein X1 represents halogen or nitro; X2 represents hydrogen, halogen, amino, hydroxy, methoxy, or the like; A and D each represent N or C—R7 (wherein R7═H, F, OCH3, or the like); R1 represents C1-C4 alkyl, C3-C6 cycloalkyl, or the like; R2 represents hydroxy, methoxy, benzyloxy, or the like; R9 represents hydrogen or C1-C3 alkyl; and R11 represents hydrogen, methyl, or CH2F; and T represents the following formula 15:
wherein B represents amino, hydroxy, or the like; and R6 represents hydrogen or methyl. The definitions of substituents and the like in the compound represented by the formula 13 do not apply to the compounds of the present invention although the same symbols are used. However, Japanese Patent Laid-Open No. 8-225567 only discloses a compound represented by the following formula 16 as such a derivative where B is an amino group.

Further, Japanese Patent Laid-Open No. 8-225567 does not describe a specific compound related to the present invention.